DESCRIPTION: Cardiovascular disease remains as the Number 1 killer in western societies. Currently, ischemic damage to the heart cannot be repaired by conventional medical care therefore only palliative treatments exist. Stem cell transplantation is a promising strategy for therapeutic cardiac regeneration, but current therapies are limited by inefficient interaction between potentially beneficial cells (either exogenously transplanted or endogenously recruited) and the injured tissue. The development of new methods that achieve selective, targeted cell-cell interactions has the potential to revolutionize cardiovascular regenerative medicine. In this application, we pioneer the concept of magnetic bi-functional cell engager (MagBICE) for therapeutic cell targeting. Iron nanoparticles (Fe) are linked with Fab' fragments directed against the therapeutic cell (Fab1) and the injured cell (Fab2). The central hypothesis is that: MagBICE (Fab1-Fe-Fab2) delivered systemically will capture mobilized stem cells in the blood and redirect them to injured tissue via the circulatory system (see cartoon illustration). MagBICE enables molecular recognition (via Fab') and physical enrichment by external magnetic field (via Fe). Moreover, translatability of the proposed MagBICE approach to human patients should be straightforward, given that both the iron nanocore and recombinant human antibodies are in human applications. We have reduced the concept into practice in preliminary studies that form the basis for this application. We have shown: Successful conjugation of whole antibodies to FDA-approved Feraheme(r) iron nanoparticles to MagBICE; MagBICE displays desirable physicochemical features for intravenous applications; MagBICE exhibits minimal cytotoxicity and specific binding to stem cells and injured cardiomyocyte in vitro; In a proof-of-concept animal study using a rat model of acute myocardial infarction (MI), intravenously-infused MagBICE captures circulating stem cells and targets them to the injured heart, reducing scar formation and rescuing cardiac function of the animals; Antibody-mediated targeting can be synergistically coupled by magnetic attraction to further enhance cell homing and the functional benefit of MagBICE. Under the auspices of this R01 award, we seek to take advantage of the latest antibody processing technologies to create a new class of MagBICE using Fab' fragments and comprehensively study their therapeutic potencies in a rat model of acute MI. Furthermore, we plan to study the toxicity of MagBICE in animals and the synergistic benefits from magnetic focusing. Unlike conventional stem cell therapies which require exogenous cell processing and transplantation, the innovation of MagBICE is the potential to recruit a person's own endogenous stem cells and efficiently target them to the site of injury. By varying the Fab' fragments attached, and/or adding a drug payload onto the iron core, MagBICE becomes a generalizable platform technology broadly applicable to a myriad of tissue degeneration diseases involving the recruitment of endogenous stem cells to the site of injury.